Process for the synthesis of azetidinones

ABSTRACT

This invention provides a process for preparing azetidinones useful as intermediates in the synthesis of penems and as hypocholesterolemic agents, particularly for azetidinones substituted in the C-3 and C-4 positions and optionally substituted at the ring nitrogen, comprising reacting a β-(substituted-amino)amide, a β-(substituted-amino)acid ester, or a β-(substituted-amino)thiolcarbonic acid ester with a silylating agent and a cyclizing agent.

The present application is the United States national applicationcooresponding to International Application No. PCT/US 94/07291, filedJul. 1, 1994 and designating the United States, which PCT application isin turn a continuation-in-part of U.S. application Ser. No. 08/089,357,filed Jul. 9, 1993, abandoned, the benefit of which applications areclaimed pursuant to the provisions of 35 U.S.C. 120, 363 and 365 (C).

BACKGROUND

This invention relates to a process for producing azetidinones useful ashypocholesterolemic agents and as intermediates for the synthesis ofpenems.

WO 93/02048 discloses stereoselective processes for producingazetidinones. One process for preparing azetidinones wherein thesubstituents at the C-3 and C-4 positions have trans relativestereochemistry comprises cyclizing a hydroxyamide prepared from acarboxylic acid, an aidehyde and an amine in a process using anoxazolidinone as a chiral auxiliary, The disclosed process comprises thefollowing steps:

(a) reacting a carboxylic acid with a chlorinating agent;

(b) deprotonating a chiral oxazolidinone, preferablyR-(+)-4-benzyloxazolidinone, with a strong base or a tertiary amine baseand treating the resulting anion with the product of step (a);

(c) enolizing the product of step (b) with either:

(i) a dialkylboron triflate and a tertiary amine base; or

(ii) TiCl₄ and tetramethylethylenediamine (TMEDA) or a mixture of TMEDAand triethylamine,

then condensing with an aldehyde;

(d) hydrolyzing the product of step (c) with a base and hydrogenperoxide;

(e) condensing the product of step (d) with an amine by treating with adehydrative coupling agent, optionally adding an activating agent; and

(f) cyclizing the product of step (e) by reacting the product of step(e) with:

(i) a dialkylazodicarboxylate and a trialkylphosphine; or

(ii) a di- or tri-chiorobenzoyl chloride, an aqueous solution of a baseand a phase transfer catalyst, then treating the resulting di- ortri-chlorobenzoate with an aqueous solution of a base and a phasetransfer catalyst; or

(iii) a dialkylchlorophosphate, an aqueous solution of a base and aphase transfer catalyst; or

(iv) a di- or tri-chlorobenzoyl chloride and a metal hydride.

In another process of WO 93/02048, an azetidinone having trans relativestereochemistry as described above is prepared by cyclizing aβ-aminoamide derivative prepared from a carboxylic acid and an imine ina process using an oxazolidinone, preferably S-phenyl-oxazolidinone, asa chiral auxiliary. This process comprises the steps:

(a) reacting a carboxylic acid with a chlorinating agent;

(b) deprotonating a chiral oxazolidinone, preferablyS-phenyl-oxazolidinone, with a strong base or a tertiary amine base andtreating the resulting anion with the product of step (a);

(c) enolizing the product of step (b) with TiCl₄ andtetramethyl-ethylenediamine (TMEDA), then condensing with an imine; and

(d) cyclizing the product of step (c) by treating with a strongnon-nucleophilic base, preferably an alkali metalbistrimethylsilylamide.

SUMMARY OF THE INVENTION

This invention provides a simple, high-yielding process for producingazetidinones under neutral conditions. Azetidinones are useful ashypocholesterolemic agents, as disclosed in WO 93/02048 and PCTInternational Application No. PCT/US94/00421, and are also useful asintermediates in the synthesis of penems, a known group ofantibacterials. This process is applicable for preparing azetidinoneswhich are optionally mono-, di- or unsubstituted at each of the C-3 andC-4 positions and substituted at the ring nitrogen. The stereochemistryof C-3, C-4-disubstituted azetidinones prepared by this process isdependent on the starting material: racemic, stereospecific orenantiomeric compounds can be obtained when the corresponding startingmaterials are used. In particular, this process is useful for thestereospecific preparation of azetidinones substituted in the C-3 andC-4 positions, and optionally substituted at the ring nitrogen.

In its broadest aspect, this invention relates to a process forpreparing an azetidinone comprising reacting aβ-(substituted-amino)-amide, a β-(substituted-amino)acid ester, or aβ-(substituted-amino)-thiolcarbonic acid ester with a silylating agentand a cyclizing agent.

More particularly, this invention relates to a process for preparing anazetidinone comprising reacting a silylating agent and a fluoride ioncatalyst cyclizing agent with a suitably protected compound selectedfrom the group consisting of

i) a β-(substituted-amino)amide, wherein the carbamoyl portion isB--C(O)--, wherein B is a deprotonated chiral auxiliary selected fromthe group consisting of ##STR1## wherein X is --O--, --S-- or --N(C₁ -C₆alkyl)-; Y is ═O or ═S; and R¹² and R¹³ are independently selected fromthe group consisting of C₁ -C₆ alkyl, phenyl, naphthyl, substitutedphenyl, substituted naphthyl, lower alkoxy-carbonyl and benzyl, whereinthe substituents on the phenyl and naphthyl are 1-3 substituentsselected from the group consisting of lower alkyl, phenyl and benzyl, orwherein one of R¹² or R¹³ is as defined above and the other is hydrogen;or B is (R¹⁴)(R¹⁵)N--, wherein R¹⁴ and R¹⁵ are independently selectedfrom the group consisting of lower alkyl, aryl and benzyl;

ii) a β-(substituted-amino)acid ester, wherein the carboxylic acid esterportion is R¹⁴ --S--C(O)--, wherein R¹⁴ is lower alkyl, aryl or benzyl;and

iii) a β-(substituted-amino)thiolcarbonic acid ester, wherein thethiolcarbonic acid ester portion is R¹⁴ --S--C(O)--, wherein R¹⁴ islower alkyl, aryl or benzyl.

Alternatively, when B is a deprotonated chiral auxiliary as definedabove, the cyclization can be effected by the addition of a monovalentsalt of the chiral auxiliary, i.e., a compound of the formula ##STR2##wherein X, Y, R¹² and R¹³ are as defined above and Z is selected fromthe group consisting of quaternary ammonium cations, such asarylalkyl-alkylammonium, aryl-alkylammonium and tetraalkylammonium, ormixtures thereof, and alkali metals, Examples of arylalkyl-alkylammoniumgroups are benzyltriethyl-ammonium and benzyl-trimethylammonium;examples of aryl-alkyl-ammonium are phenyltriethylammonium andphenyltrimethyl-ammonium; typical tetraalkylammonium groups containalkyl groups of 1-6 carbon atoms, e.g., tetra n-butylammonium; andtypical alkali metals are sodium, potassium, cesium and lithium.

The process using a starting material wherein theβ-(substituted-amino)amide comprises a deprotonated chiral auxiliary asdefined above in (i) can alternatively be used with a non-chiralauxiliary, i.e., an auxiliary as defined above wherein each of R¹² andR¹³ are hydrogen. The process employing a non-chiral auxiliary in thestarting material can employ either a fluoride ion catalyst or a salt ofa chiral or non-chiral auxiliary for cyclization. Also, a salt of anon-chiral auxiliary can be used as a cyclizing agent in a process usinga starting material containing a chiral auxiliary.

A particularly preferred embodiment of this invention relates to aprocess for preparing an azetidinone, especially a stereospecificazetidinones as disclosed in WO 93/02048 and PCT/US94/00421, representedby structural formula I ##STR3##

wherein

Q is hydrogen, lower alkyl; phenyl-(CH₂)₀₋₃ - or(W-substituted)phenyl-(CH₂)₀₋₃ ;

R is phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl,benzodioxolyl, heteroaryl, W-substituted heteroaryl, benzofusedheteroaryl and W-substituted benzofused heteroaryl, wherein heteroarylis selected from the group consisting of pyrrolyl, pyridinyl,pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl,thienyl, oxazolyl and furanyl, and for nitrogen-containing heteroaryls,the N-oxides thereof;

R¹ and R² are independently selected from H or R;

W is 1 to 3 substituents independently selected from the groupconsisting of lower alkyl, hydroxy lower alkyl, lower alkoxy,alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxy, (loweralkoxyimino)-lower alkyl, lower alkylenedioyl, lower alkyl loweralkylenedioyl, allyloxy, --CF₃, --OCF₃, benzyl, R³ -benzyl, benzyloxy,R³ -benzyloxy, phenoxy, R³ -phenoxy, dioxolanyl, NO₂, --NR⁴ R⁵, NR⁴ R⁵(lower alkyl)-, NR⁴ R⁵ (lower alkoxy)-, OH, halogeno, --NHC(O)OR⁶,--NHC(O)R⁶, R⁷ O₂ SNH--, (R⁷ O₂ S)₂ N--, --S(O)₂ NH₂, --S(O)₀₋₂ R⁴,tert-butyldimethyl-silyloxymethyl, ##STR4##

A and D are independently a bond; C₃ -C₆ cycloalkylene; C₁ -C₁₀alkylene; C₁ -C₁₀ alkenylene; C₁ -C₁₀ alkynylene; an alkylene,alkenylene or aikynylene chain as defined substituted by one or moresubstituents independently selected from the group consisting of phenyl,W-substituted phenyl, heteroaryl and W-substituted heteroaryl, whereinheteroaryl is as defined above; an alkylene, alkenylene or alkynylenechain as defined interrupted by one or more groups independentlyselected from the group consisting --O--, --S--, --SO--, --SO₂ --,--NR₈, --C(O)--, C₃ -C₆ cycloalkylene, phenylene, W-substitutedphenylene, heteroarylene and W-substituted heteroarylene; or aninterrupted alkylene, alkenylene or alkynylene chain as definedsubstituted by one or more substituents independently selected from thegroup consisting of phenyl, W-substituted phenyl, heteroaryl andW-substituted heteroaryl; or R² -D is selected from the group consistingof halogeno, OH, lower alkoxy, --OC(O)R⁶, --NR⁴ R⁵, --SH and --S(loweralkyl);

R³ is 1-3 groups independently selected from the group consisting oflower alkyl, lower alkoxy, --COOH, NO₂, --NR⁴ R⁵, OH or halogeno;

R⁴ and R⁵ are independently selected from H and lower alkyl;

R⁶ is lower alkyl, phenyl, R³ -phenyl, benzyl or R³ -benzyl;

R⁷ is OH, lower alkyl, phenyl, benzyl, R³ -phenyl or R³ -benzyl; R⁸ isH, OH, alkoxy, phenoxy, benzyloxy, ##STR5## lower alkyl, phenyl or R³-phenyl;

R⁹ is --O--, --CH₂ --, --NH-- or --N(lower alkyl)-;

or Q and R² --D-- together form the group ##STR6##

wherein R¹⁸ is ##STR7##

R¹⁶ and R¹⁷ are independently selected from the group consisting of--CH₂ --, --CH(lower alkyl)-, --C(di-lower alkyl)-, --CH═CH-- and--C(lower alkyl)═CH--; or R¹⁸ together with an adjacent R¹⁶, or R¹⁸together with an adjacent R¹⁷, form a --CH═CH-- or a --CH═C(loweralkyl)- group;

u and v are independently 0, 1, 2 or 3. provided both are not zero;provided that when R¹⁶ is --CH═CH-- or --C(lower alkyl)═CH--, v is 1;provided that when R¹⁷ is --CH═CH-- or --C(lower alkyl)═CH--, u is 1;provided that when v is 2 or 3, the R¹⁶ 's can be the same or different;and provided that when u is 2 or 3, the R¹⁷ s can be the same ordifferent; and

q is 0, 1, 2, 3, 4, 5 or 6; comprising reacting a compound of formula II##STR8##

wherein A, D, Q, R, R¹ and R² are as defined above and G is B,(R¹⁴)--O-- or (R¹⁴)--S--, wherein B and R¹⁴ are as defined above, with asilylating agent and a fluoride ion catalyst cyclizing agent or, when Bis a chiral auxiliary, with a silylating agent and a salt of said chiralauxiliary, provided that where substituents A, D, Q, R, R¹ and R²include substituents selected from the group consisting of --NH₂, --SHand --OH, said substituents are suitably protected prior to reactionwith the silylating agent.

A particularly preferred embodiment of the present invention relates tothe preparation of compounds of formula I wherein Q is hydrogen and thesubstitutents R² --D-- and R¹ --A-- have trans relative stereochemistry,wherein said process comprises reacting a compound of formula IIa##STR9##

wherein A, D, R, R¹ and R² are as defined above and G is B, (R¹⁴)--O--or (R¹⁴)--S--, wherein B and R¹⁴ are as defined above, with a silylatingagent and a fluoride ion catalyst cyclizing agent or, when B is a chiralauxiliary, with a silylating agent and a salt of said chiral auxiliary,provided that where substituents A, D, R, R¹ and R² include substituentsselected from the group consisting of --NH₂, --SH and --OH, saidsubstituents are suitably protected prior to reaction with thesilylating agent.

DETAILED DESCRIPTION

As used herein, the terms β-(substituted-amino)amide,β-(substituted-amino)acid ester, and β-(substituted-amino)thiolcarbonicacid ester refer to β-aminoamides, β-aminoacid esters, andβ-aminothiolcarbonic acid esters refer to secondary amines, that is,compounds wherein the nitrogen is joined to the β-carbon, to a hydrogenmolecule, and to a non-hydrogen substituent.

"Aryl" means phenyl, W-substituted phenyl, naphthyl or W-substitutednaphthyl.

As used herein, the term "lower alkyl" means straight or branched alkylchains of 1 to 6 carbon atoms and "lower alkoxy" similarly refers toalkoxy groups having 1 to 6 carbon atoms;

"Alkenyl" means straight or branched carbon chains having one or moredouble bonds in the chain, conjugated or unconjugated, and alkadienylrefers to chains having two double bonds in the chain; similarly,"alkynyl" means straight or branched carbon chains having one or moretriple bonds in the chain.

Where an alkyl, alkenyl or alkynyl chain joins two other variables andis therefore bivalent, the terms alkylene, alkenylene and alkynylene areused.

"Cycloalkyl" means a saturated carbon ring of 3 to 6 carbon atoms, while"cycloalkylene"refers to a corresponding bivalent ring, wherein thepoints of attachment to other groups include all positional isomers.

"Halogeno" refers to fluorine, chlorine, bromine or iodine radicals.

"Heteroaryl" includes all positional isomers for a given heteroarylgroup as defined above, for example 2-pyridyl, 3-pyridyl and 4-pyridyl.Benzofused heteroaryl refers to radicals formed by the bonding of abenzene radical to adjacent carbon atoms on a heteroaryl ring; examplesare indolyl, quinolyl, quinazolinyl, quinoxalinyl, benzotriazolyl,indazolyl, benzoxazolyl, benzothienyl and benzofuranyl.

"Phenylene" means a bivalent phenyl group bound in an ortho, meta orpara orientation and "heteroarylene" similarly means a bivalentheteroaryl group, including all positional isomers.

"(Lower alkoxyimino)lower alkyl" refers to the group (C₁ -C₆ loweralkoxy)-N═CH-(C₁ -C₅ lower alkyl). "Lower alkylenedioyl" means radicalsof the formula --OC(O)(CH₂)₁₋₄ C(O)OH, while "lower alkyl loweralkylenedioyl" means radicals of the formula --OC(O)(CH₂)₁₋₄C(O)O-(lower alkyl).

R³ -benzyl and R³ -benzyloxy refer to benzyl and benzyloxy radicalswhich are substituted on the phenyl ring.

The carbon chains as defined in A and D, when substituted by optionallysubstituted phenyl or heteroaryl groups, may include independentsubstitution on different carbon atoms, di-substitution on one carbonatom, or both. One skilled in the art will recognize that the number ofdouble or triple bonds present, the replacement of carbon atoms in thechain and the presence of substitutents on the carbon atoms in the chainare all dependent on the length of the chain: shorter carbon chainscannot accommodate as many double or triple bonds, carbon replacementsor substituents as longer carbon chains can. In general, unsaturatedcarbon chains contain 1 to 4 double or triple bonds, conjugated ornon-conjugated. Where carbon atoms are replaced, 1 to 4 replacementgroups can be present. Similarly, when carbon atoms in the chain aresubstituted, 1 to 4 substituents can be present.

Examples of alkylene chains in A and D are methylene, ethylene,propylene, butylene and decylene.

Examples of unsaturated A and D groups are ethenylene and acetylene.

Examples of A and D groups wherein the carbon atoms in the chain arereplaced are --CH₂ CH₂ O--, --OCH₂ CH₂ --, --CH₂ O--, --CH₂ CH₂ CH₂ O--,--CH₂ --O--CH₂ --, --CH₂ CH₂ --O--CH₂, --CH₂ CH₂ --NH--, --CH₂ CH₂ --N(CH₃)-- and --O--CH₂ C(O)--NH--.

Azetidinones prepared by this process, and in particular compounds offormula I, may have at least two asymmetrical carbon atoms and thereforethe preparation of all isomers, including diastereomers and rotationalisomers, is contemplated. The compounds prepared by this inventioninclude d and I isomers in both pure form and in admixture, includingracemic mixtures. Isomeric compounds prepared by this invention may alsoinclude geometric isomers, e.g. when A or D in compounds of formula Icontains a double bond.

The order of addition of the components of this process is not criticalto the preparation of the azetidinone product. For example, the startingβ-(substituted-amino)amide, β-(substituted-amino)acid ester, orβ-(substituted-amino)thiolcarbonic acid ester can first be reacted withthe silylating agent and then reacted with the cyclizing agent, or thestarting compound can be added to a mixture of the silylating agent andthe cyclizing agent.

Silylation is effected by reacting the starting material with asilyl-enol ether silylating agent such as bistrimethylsilyl acetamide(BSA), N-methyl-O-trimethylsilyl acetamide or iso-propenyloxytrimethylsilane, preferably BSA, in a suitable inert organic solvent at0° C. to 110° C., preferably at about 20° C. to 90° C., and morepreferably at ambient temperature (e.g., about 25° C.). The reaction ispreferably carried out in a dry, inert atmosphere, e.g., the solvent isdried, typically with molecular sieves, and the reaction is carried outunder nitrogen. When the silylation and cyclization are donesequentially, i.e., the silylating agent is reacted with the startingmaterial first, the silylation reaction can be allowed to continue forup to about two hours, but preferably the cyclization step is carriedout immediately after silylation, or the silylating agent and thecyclizing agent are added simultaneously.

Those skilled in the art will recognize that for cyclization to proceedas desired, --NH₂, --SH and --OH substituents present on theβ-(substituted-amino)amide, a β-(substituted-amino)acid ester, or aβ-(substituted-amino)thiolcarbonic acid ester starting material must beconverted to groups which will not be silylated, either preferentiallyor in addition to silylation of the substituted-amino portion of themolecule (i.e., --NH--R in formula II). Suitable protecting groups wellknown in the art include for --NH₂ : t-butyldimethylsilyl, benzyl,benzoyl and t-butoxycarbonyl; for --SH: triphenylmethyl; and for --OH:lower alkoxy, e.g., methoxy, benzyloxy and t-butyldimethylsilyl.

The source of the fluoride ion used to catalyze the intra-molecularcyclization is typically a quaternary alkyl-, aryl-alkyl- orarylalkyl-alkylammonium fluoride salt or a hydrate thereof, or a mixturethereof, wherein alkyl-, aryl-alkyl- or arylalkyl-alkylammonium are asdefined above for Z, or is an alkali metal fluoride salt or a hydratethereof, such as cesium fluoride or potassium fluoride. When a hydratedquaternary ammonium fluoride salt is used, the reagent is added in acatalytic amount, i.e., about 1 to about 20 mole percent, preferablyabout 5 mole percent, and when an anhydrous quaternary ammonium fluoridesalt is used, it can be added in a catalytic up to a stoichiometricamount. When an alkali metal fluoride salt is used, it is added incatalytic amount up to a stoichiometric amount compared to the startingβ-amino compound, depending on the solubility of the reagent in thesolvent used (higher solubility requires less reagent). If added to thereaction mixture after the silylation agent, the fluoride reagent isadded directly to the reaction mixture resulting from silylation, and isreacted at about 0° C. to 110° C., preferably about 20° C. to 60° C.,for about 0.5 to about 6 hours, preferably about 1 hour. When thesilylation reagent and the fluoride reagent are added simultaneously,the reaction is conducted under similar conditions.

Alternatively, for cyclizing compounds wherein the starting β-aminocompound contains a chiral auxiliary, a salt of the chiral auxiliary asdefined above may be used instead of the fluoride ion to catalyze thereaction. The chiral auxiliary-containing β-amino compound is reacted atroom temperature up to reflux temperature for 1 hour with a silylatingreagent as described above under an inert atmosphere, e.g., N₂, in asuitable inert solvent. The chiral auxiliary salt can be added to thereaction mixture at the same time as the silylating agent, or it can beadded directly to the reaction mixture resulting from silylation in acatalytic amount or in a stoichiometric amount compared to the startingβ-amino compound, and the mixture is reacted at about 0° C. to 110° C.,preferably about 20° to 60° C. for an additional hour.

The azetidinone resulting from either the fluoride ion or chiralauxiliary salt process can be purified by appropriate standardprocedures such as column chromatography or crystallization.

The term "suitable inert organic solvent" as used above means anyorganic solvent or combination of solvents that is unreactive in thereaction being conducted and is a solvent for the reactants. Typicalsuitable solvents are halogenated compounds such as dichloromethane;heterocyclic compounds such as tetrahydrofuran (THF); DMSO;dimethyl-formamide (DMF); acetonitrile; and carbocyclic aromatics suchas toluene. Preferred are toluene, THF and dichloromethane.

Starting β-(substituted-amino)amides, β-(substituited-amino)acid estersand β-(substituted-amino)thiolcarbonic acid esters are known or can beprepared by one skilled in the art using known methods. β-aminoamidecompounds of formula II and IIa, wherein B is a radical of a chiralauxiliary, are disclosed in WO 93/02048.

The chiral auxiliary salt is prepared by known procedures, for examplethe tetra n-butylammonium salt of a 2-oxazolidinone can be prepared bydeprotonating the chiral auxiliary with a strong base such as sodiumhydride in an inert solvent such as THF at 0° C. for 30 minutes, thenadding the tetra n-butylammonium chloride or bromide salt and stirringfor an additional 30 minutes.

An especially preferred embodiment of the process of this inventioncomprises the reaction of a β-(substituted-amino)amide of formula IIb,i.e., a compound of formula IIa wherein G is B', a deprotonated chiralauxiliary as defined above; use of a chiral auxiliary as part of thestarting β-(substituted-amino)amide is particularly desirable becausethe salt of the chiral auxiliary resulting from the process can berecovered for reuse. A more preferred embodiment, exemplified by thepreparation of compounds of formula I wherein the C-3 and C-4substitutents have trans relative stereochemistry, is shown in Scheme A.Said process comprises the reaction of a compound of formula IIb,wherein A, D, X, Y, R, R¹, R², R¹² and R¹³ are as defined above, with asilylating agent and a fluoride ion to prepare a compound of formula Ia,wherein Q is hydrogen. ##STR10## In the reaction shown in Scheme A, itis preferred that in the starting material of compound IIb, X and Y areeach oxygen and R¹² is hydrogen. More preferred compounds of formula IIbare those wherein X and Y are each oxygen, R¹² is hydrogen and R¹³ isphenyl, benzyl or isopropyl. A preferred silylating agent is BSA, and apreferred source of fluoride ion is tetra n-butylammonium fluoride or ahydrate thereof, preferably its trihydrate.

The following examples illustrate the process of this invention.Although the examples are directed to C-3, C-4 disubstituted compoundsand the stereochemistry of the reactants and intermediates are indicatedin the various depicted structural formulas in the following examples,it is to be understood that the process of this invention is operativefor azetidinones regardless of stereochemistry, and involves merely theselection of reactants having the desired racemic or stereochemicalconfiguration and the selection of reaction conditions which result inthe desired configuration in the product.

Preparation 1 PhCH₂ CH₂ CH₂ CH₂ COOH+SOCl₂ →PhCH₂ CH₂ CH₂ CH₂ COCl

Step A: To a stirred suspension of 5-phenyl valeric acid (50 g, 281mmol) in toluene (50 mL), add SOCl₂ (40 mL, 548 mmol). Heat the mixtureto 90° C. in an oil bath for 3 hours. Distill off the excess SOCl₂ as anazeotropic mixture with toluene under reduced pressure. Again addtoluene (50 mL), and distill off both toluene and any residual SOCl₂under reduced pressure. Add CH₂ Cl₂ (200 mL) to the crude acid chloridein the reaction flask and use the resulting solution directly in Step B.##STR11##

Step B: To CH₂ Cl₂ (600 mL), add (4S)-4-phenyl-2-oxazolidinone (38.6 g,236.8 mmol), triethylamine (TEA) (80 mL, 574 mmol) and 4-dimethyl-aminopyridine (DMAP) (2 g, 16.4 mmol). Stir the mixture and cool in anice-bath to ˜5° C. Slowly add the solution of Step A, maintaining thetemperature at ˜5° C. After the addition is complete, allow the mixtureto warm to room temperature and stir overnight. Add water (400 mL) andstir for 30 minutes to destroy the excess acid chloride. Separate theorganic layer and extract the aqueous layer with CH₂ Cl₂ (200 mL).Combine the organic layers, wash with aqueous 2N H₂ SO₄ (600 mL),followed by brine solution (200 mL), saturated NaHCO₃ (400 mL) and brinesolution (200 mL). Concentrate the organic layer under reduced pressure,and dissolve the resultant residue in CH₂ Cl₂ to a total volume of 1000mL. Use this solution in Step C. ##STR12##

Step C: Cool a solution of the product of Step B (238 mL, 56.4 mmol) inCH₂ Cl₂ to -20° C. to -25° C. Slowly add a I molar solution of TiCl₄ inCH₂ Cl₂ (56 mL, 56 mmol), while maintaining the temperature below -20°C. After the addition is complete, stir for 10 min. at that temperature.Slowly add Hunig's base (N,N-diisopropylethylamine) (19.5 mL, 112 mmol);a characteristic dark-red color is observed. Stir the mixture for 30min. at -20° to -25° C. Slowly add a solution of Schiff's base derivedfrom anisaldehyde and p-anisidine (26.86 g, 111.5 mmol) in CH₂ Cl₂ (200mL) and stir for 1 hour while maintaining the temperature below -20° C.Quench the reaction by adding a solution of glacial acetic acid (18 mL)in CH₂ Cl₂ (32 mL), maintaining the temperature below -20° C. Continuestirring for 30 min., then pour the reaction mixture into aqueous 2N H₂SO₄ (600 mL ) at 0° C. Stir for 30 minutes, then add ethyl acetate(EtOAc)(1 L) and stir until the organic layer separates cleanly.Separate the organic layer, extract the aqueous layer with CH₂ Cl₂ (50mL), combine the organic layers and wash with saturated NaHCO₃ solution,followed by brine solution. Concentrate the organic layer under reducedpressure and crystallize the residue from EtOAc and hexane to obtain thepure (β-amino carbonyl compound of formula 1.

EXAMPLE 1 ##STR13##

To a stirred suspension of the β-aminoamide of formula 1 (15 g, 26.6mmol) in sieve-dried toluene (225 mL) at about 90° C. under a N₂atmosphere, add BSA (10 mL, 40.5 mmol) and heat the reaction mixture forabout one hour at about 90° C. Add tetra n-butylammonium fluoridetrihydrate (420 mg, 1.33 mmol) and heat for one hour at 90° C. to obtain10.2 g of the compound of formula Ia (96% yield), 99% de, 99.9% ee.

EXAMPLE 1A

To a stirred suspension of the β-aminoamide of formula 1 as shown inExample 1 (20 g, 35.5 mmol) in sieve-dried toluene (400 mL) at about 90°C. under a N₂ atmosphere, add BSA (15 mL, 60.75 mmol) and heat at about90° C. for 2 hours. Cool to 55°-60° C., add tetra n-butylammoniumfluoride trihydrate (560 mg, 1.78 mmol) and heat for 2 hours at 55°-60°C. to obtain 13.62 g of the compound of formula Ia as shown in Example 1(96% yield), 99% de, 99.9% ee.

EXAMPLE 1B

To a stirred suspension of the β-aminoamide of formula 1 as shown inExample 1 (20 g, 35.5 mmol) in toluene (200 mL) at room temperature, addBSA (15 mL, 60.75 mmol), followed by tetra n-butylammonium fluoridetrihydrate (112 mg, 0.35 mmol). Monitor the reaction progress by HPLC;after 1.5 h, obtain compound 1a (14.2 g, 99.8% yield) 99% de, 99.9% ee.

EXAMPLE 1C

To a stirred suspension of the β-aminoamide of formula 1 as shown inExample 1 (5.014 g, 8.9 mmol) in DMSO (35 mL) at room temperature, addBSA (3.8 mL, 15.2 mmol), followed by CsF (68 mg, 0.445 mmol). Monitorthe reaction progress by HPLC; add additional BSA (2 mL) and stir 4 h toobtain compound 1a (2.8 g, 79% yield) 96% de, 99.9% ee.

EXAMPLE 2 ##STR14##

To a stirred suspension of the β-aminoamide of formula 2 (5 g, 8.9 mmol)in dry THF (75 mL), add BSA (5.4 mL, 21.85 mmol), then reflux under a N₂atmosphere for 16 hours. Add anhydrous CsF (1.35 g, 8.9 mmol) and refluxfor 6 hours to obtain 3.42 g of the compound of formula Ib (96% yield),99% de.

EXAMPLE 2A ##STR15##

Step 1: To a stirred solution of (R)-4-phenyl-2-oxazolidinone (174 mg,1.06 mmol) in THF (4 mL) at 0° C., add NaH (4.3 mg, 60% emulsion in oil,0.106 mmol). Allow the temperature to rise to room temperature over 30min., then add tetra n-butylammonium bromide (34 mg, 0.106 mmol) to themixture and stir for another 30 min. to obtain(R)-4-phenyl-2-oxazolidinone tetra n-butylammonium salt.

Step 2: To a stirred solution of the β-aminoamide of formula 2 (0.604 g,1.06 mmol) in sieve-dried THF (8 mL) at reflux under an N₂ atmosphere,add BSA (0.66 mL, 2.66 mmol). Heat to reflux for 1 h, then add asolution of the product of Step 1 (0.106 mmol) in THF (4 mL). Continueheating for 1 h to obtain the product 1b (0.37 g, 87% yield) 97% de,99.9% ee.

In a similar manner, at reflux or at room temperature, use(S)-4-phenyl-2-oxazolidinone tetra n-butylammonium salt and compound 1of Preparation 1 to prepare compound Ia.

We claim:
 1. A process for preparing an azetidinone represented by theformula ##STR16## wherein Q is hydrogen, lower alkyl, phenyl-(CH₂)₀₋₃ -or (W-substituted)-phenyl-(CH₂)₀₋₃ ;R is phenyl, W-substituted phenyl,naphthyl, W-substituted naphthyl, benzodioxolyl, heteroaryl,W-substituted heteroaryl, benzofused heteroaryl and W-substitutedbenzofused heteroaryl, wherein heteroaryl is selected from the groupconsisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl,imidazolyl, thiazolyl, pyrazolyl, thienyl, oxazolyl and furanyl, and fornitrogen-containing heteroaryls, the N-oxides thereof; R¹ and R² areindependently selected from H or R; W is 1 to 3 substituentsindependently selected from the group consisting of lower alkyl, hydroxylower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy,alkoxycarbonylalkoxy, (lower alkoxyimino)-lower alkyl, loweralkylenedioyl, lower alkyl lower alkylenedioyl, allyloxy, --CF₃, --OCF₃,benzyl, R³ -benzyl, benzyloxy, R³ -benzyloxy, phenoxy, R³ -phenoxy,dioxolanyl, NO₂, --NR⁴ R⁵, NR⁴ R⁵ (lower alkyl)-, NR⁴ R⁵ (loweralkoxy)-, OH, halogeno, --NHC(O)OR⁶, --NHC(O)R⁶, R⁷ O₂ SNH--, (R⁷ O₂ S)₂N--, --S(O)₂ NH₂, --S(O)₀₋₂ R⁴, tert-butyldimethyl-silyloxymethyl,--C(O)R⁸, ##STR17## A and D are independently a bond; C₃ -C₆cycloalkylene; C₁ -C₁₀ alkylene; C₂ -C₁₀ alkenylene; C₂ -C₁₀ alkynylene;an alkylene, alkenylene or alkynylene chain as defined substituted byone or more substituents independently selected from the groupconsisting of phenyl, W-substituted phenyl, heteroaryl and W-substitutedheteroaryl, wherein heteroaryl is as defined above; an alkylene,alkenylene or alkynylene chain as defined interrupted by one or moregroups independently selected from the group consisting of --O--, --S--,--SO--, --SO₂ --, --NR₈, --C(O)--, C₃ -C₆ cycloalkylene, phenylene,W-substituted phenylene, heteroarylene and W-substituted heteroarylene;or an interrupted alkylene, alkenylene or alkynylene chain as definedsubstituted by one or more substituents independently selected from thegroup consisting of phenyl, W-substituted phenyl, heteroaryl andW-substituted heteroaryl; or R² -D is selected from the group consistingof halogeno, OH, lower alkoxy, --OC(O) R⁶, --NR⁴ R⁵, --SH and --S(loweralkyl); R³ is 1-3 groups independently selected from the groupconsisting of lower alkyl, lower alkoxy, --COOH, NO₂, --NR⁴ R⁵, OH orhalogeno; R⁴ and R⁵ are independently selected from H and lower alkyl;R⁶ is lower alkyl, phenyl, R³ -phenyl, benzyl or R³ -benzyl; R⁷ is OH,lower alkyl, phenyl, benzyl, R³ -phenyl or R³ -benzyl; R⁸ is H, OH,alkoxy, phenoxy, benzyloxy, ##STR18## --NR⁴ R⁵, lower alkyl, phenyl orR³ -phenyl; R⁹ is --O--, --CH₂ --, --NH-- or --N(lower alkyl)-; or Q andR² --D-- together form the group ##STR19## wherein R¹⁸ is ##STR20## R¹⁶and R¹⁷ are independently selected from the group consisting of --CH₂--, --CH(lower alkyl)-, --C(di-lower alkyl)-, --CH═CH-- and --C(loweralkyl)═CH--; or R¹⁸ together with an adjacent R¹⁶, or R18 together withan adjacent R¹⁷, form a --CH═CH-- or a --CH═C(lower alkyl)- group; u andv are independently 0, 1, 2 or 3, provided both are not zero; providedthat when R¹⁶ is --CH═CH-- or --C(lower alkyl)═CH--, v is 1; providedthat when R¹⁷ is --CH═CH-- or --C(lower alkyl)═CH--, u is 1; providedthat when v is 2 or 3, the R¹⁶ 's can be the same or different; andprovided that when u is 2 or 3, the R¹⁷ 's can be the same or different;and q is 0, 1,2, 3, 4, 5 or 6; comprising reacting a compound of formulaII ##STR21## wherein A, D, Q, R, R¹ and R² are as defined above and G isB, wherein B is a deprotonated chiral auxiliary selected from the groupconsisting of ##STR22## wherein X is --O--, --S-- or --N(C₁ C₆ alkyl)-;Y is ═0 or ═S; and R¹² and R¹³ are independently selected from the groupconsisting of C₁ -C₆ alkyl, phenyl, naphthyl, substituted phenyl,substituted naphthyl, lower alkoxycarbonyl and benzyl, wherein thesubstituents on the phenyl and naphthyl are 1-3 substituents selectedfrom the group consisting of lower alkyl, phenyl and benzyl, or whereinone of R¹² or R¹³ is as defined above and the other is hydrogen;with asilylating agent and a fluoride ion catalyst cyclizing agent or, when Bis a deprotonated chiral auxiliary as defined above, with a silylatingagent and a salt of said chiral auxiliary, provided that wheresubstituents A, D, Q, R, R¹ and R² include substituents selected fromthe group consisting of --NH₂, --SH and --OH, said substituents aresuitably protected prior to reaction with the silylating agent.
 2. Aprocess for preparing an azetidinone represented by the formula##STR23## wherein Q is hydrogen, lower alkyl, phenyl-(CH₂)₀₋₃ - or(W-substituted)-phenyl-(CH₂)₀₋₃ ;R is phenyl, W-substituted phenyl,naphthyl, W-substituted naphthyl, benzodioxolyl, heteroaryl,W-substituted heteroaryl, benzofused heteroaryl and W-substitutedbenzofused heteroaryl, wherein heteroaryl is selected from the groupconsisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl,imidazolyl, thiazolyl, pyrazolyl, thienyl, oxazolyl and furanyl, and fornitrogen-containing heteroaryls, the N-oxides thereof; R¹ and R² areindependently selected from H or R; W is 1 to 3 substituentsindependently selected from the group consisting of lower alkyl, hydroxylower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy,alkoxycarbonylalkoxy, (lower alkoxyimino)-lower alkyl, loweralkylenedioyl, lower alkyl lower alkylenedioyl, allyloxy, --CF₃, --OCF₃,benzyl, R³ -benzyl, benzyloxy, R³ -benzyloxy, phenoxy, R³ -phenoxy,dioxolanyl, NO₂, --NR⁴ R⁵, NR⁴ R⁵ (lower alkyl)-, NR⁴ R⁵ (loweralkoxy)-, OH, halogeno, --NHC(O)OR⁶, --NHC(O)R⁶, R⁷ O₂ SNH--, (R⁷ O₂ S)₂N--, --S(O)₂ NH₂, --S(O)₀₋₂ R⁴, tert-butyldimethyl-silyloxymethyl,--C(O)R⁸, ##STR24## A and D are independently a bond; C₃ -C₆cycloalkylene; C₁ -C₁₀ alkylene; C₂ -C₁₀ alkenylene; C₂ -C₁₀ alkynylene;an alkylene, alkenylene or alkynylene chain as defined substituted byone or more substituents independently selected from the groupconsisting of phenyl, W-substituted phenyl, heteroaryl and W-substitutedheteroaryl, wherein heteroaryl is as defined above; an alkylene,alkenylene or alkynylene chain as defined interrupted by one or moregroups independently selected from the group consisting of --O--, --S--,--SO--, --SO₂ --, --NR₈, --C(O)--, C₃ -C₆ cycloalkylene, phenylene,W-substituted phenylene, heteroarylene and W-substituted heteroarylene;or an interrupted alkylene, alkenylene or alkynylene chain as definedsubstituted by one or more substituents independently selected from thegroup consisting of phenyl, W-substituted phenyl, heteroaryl andW-substituted heteroaryl; or R² -D is selected from the group consistingof halogeno, OH, lower alkoxy, --OC(O)R⁶, --NR⁴ R⁵, --SH and --S(loweralkyl); R³ is 1-3 groups independently selected from the groupconsisting of lower alkyl, lower alkoxy, --COOH, NO₂, --NR⁴ R⁵, OH orhalogeno; R⁴ and R⁵ are independently selected from H and lower alkyl;R⁶ is lower alkyl, phenyl, R³ -phenyl, benzyl or R³ -benzyl; R⁷ is OH,lower alkyl, phenyl, benzyl, R³ -phenyl or R³ -benzyl; R⁸ is H, OH,alkoxy, phenoxy, benzyloxy, ##STR25## --NR⁴ R⁵, lower alkyl, phenyl orR³ -phenyl; R⁹ is --O--, --CH² --, --NH-- or --N(lower alkyl)-; or Q andR² --D-- together form the group ##STR26## wherein R¹⁸ is ##STR27## R¹⁶and R¹⁷ are independently selected from the group consisting of --CH₂--, --CH(lower alkyl)-, --O(di-lower alkyl)-, --CH═CH-- and --C(loweralkyl)═CH--; or R¹⁸ together with an adjacent R¹⁶, or R¹⁸ together withan adjacent R¹⁷, form a --CH═CH-- or a --CH═C(lower alkyl)- group; u andv are independently 0, 1, 2 or 3, provided both are not zero; providedthat when R¹⁶ is --CH═CH-- or --O(lower alkyl)═CH--, v is 1; providedthat when R¹⁷ is --CH═CH-- or --C(lower alkyl)═CH--, u is 1; providedthat when v is 2 or 3, the R¹⁶ 's can be the same or different; andprovided that when u is 2 or 3, the R¹⁷ 's can be the same or different;and q is 0, 1, 2, 3, 4, 5 or 6; comprising reacting aβ-(substituted-amino)amide of the formula ##STR28## withbistrimethylsilylacetamide and (S)-4-phenyl-2-oxazolidinone tetran-butylammonium salt.
 3. A process of claim 1 wherein the fluoride ioncatalyst is a quaternary alkylammonium fluoride salt, a quaternaryalkylammonium fluoride salt hydrate, a quaternary arylalkyl-ammoniumfluodde salt, a quaternary arylalkyl-ammonium fluoride salt hydrate, aquaternary arylalkyl-alkyl-ammonium fluoride salt, a quaternaryarylalkyl-alkyl-ammonium fluoride salt hydrate, or a mixture thereof. 4.A process of claim 1 wherein the fluoride ion catalyst is an alkalimetal fluoride salt or hydrate thereof.
 5. A process of claim 4comprising reacting a compound of the formula ##STR29## wherein A, D, R,R¹, R², and G are as defined in claim 4, with a silylating agent and afluoride ion catalyst cyclizing agent.
 6. A process of claim 4comprising reacting a compound of the formula ##STR30## wherein A, D, R,R¹, and R² are as defined in claim 4 and G' is B', wherein B' is adeprotonated chiral auxiliary selected from the group consisting of##STR31## wherein X is --O--, --S-- or --N(C₁ -C₆ alkyl)-; Y is ═O or═S; and R¹² and R¹³ are independently selected from the group consistingof C₁ -C₆ alkyl, phenyl, naphthyl, substituted phenyl, substitutednaphthyl, lower alkoxycarbonyl and benzyl, wherein the substituents onthe phenyl and naphthyl are 1-3 substituents selected from the groupconsisting of lower alkyl, phenyl and benzyl, or wherein one of R¹² orR¹³ is as defined above and the other is hydrogen;with a a silylatingagent and a cyclizing agent which is a monovalent salt of the formula##STR32## wherein X, Y, R¹² and R¹³ are as defined above or each of R¹²and R¹³ is hydrogen, and Z is selected from the group consisting ofquaternary ammonium cations and alkali metals wherein the quaternaryammonium cations are selected from the group consisting ofarylalkyl-alkylammonium, aryl-alkylammonium, tetraalkylammonium andmixtures thereof.
 7. A process of claim 1 wherein the silylating agentis a silyl-enol ether.
 8. A process of claim 1 wherein the silylatingagent is bistrimethyisilylacetamide, N-methyl-O-trimethyl silylacetamideor isopropenyloxy trimethylsilane.
 9. A process of claim 5 comprisingreacting a β-(substituted-amino)amide of the formula ##STR33## wherein Xand Y are each oxygen, R¹² is hydrogen and R¹³ is phenyl, benzyl orisopropyl, with bistrimethylsilylacetamide and with tetran-butyl-ammonium fluoride, cesium fluoride or a hydrate thereof.
 10. Aprocess of claim 1 wherein the fluoride ion catalyst is tetran-butylammonium fluoride, cesium fluoride, potassium fluoride, or ahydrate thereof.
 11. A process for preparing a compound of the formula##STR34## comprising reacting a β-(substituted-amino)amide of theformula ##STR35## with bistrimethylsilylacetamide and with tetran-butyl-ammonium fluoride, cesium fluoride or a hydrate thereof.
 12. Aprocess for preparing a compound of the formula ##STR36## comprisingreacting a β-(substituted-amino)amide of the formula ##STR37## withbistrimethylsilylaoetamide and (S)-4-phenyl-2-oxazolidinone tetran-butylammonium salt.